A Pilot Study Assessing the Integrase Inhibitor GSK1349572 in HIV-infected Persons With Virus Resistant to Raltegravir

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Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

No text entered.

Reporting Groups

Description

Cohort I (DTG 50 mg OD)

Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).

Number of Participants Who Achieved HIV-1 RNA <400 Copies (c)/Milliliter (mL) or at Least 0.7 log10 c/mL Below Their Baseline Value at Day 11 [ Time Frame: Baseline (Day 1) and Day 11 ]

Measure Type

Primary

Measure Title

Number of Participants Who Achieved HIV-1 RNA <400 Copies (c)/Milliliter (mL) or at Least 0.7 log10 c/mL Below Their Baseline Value at Day 11

Measure Description

The number of participants who acheived Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) <400 c/mL or at least 0.7 log10 c/mL below their Baseline value at Day 11 was assessed. The last observation was carried forward if a participant had missed the Day 11 visit. The Baseline observation was carried forward if a participant had discontinued the treatment before Day 11. Blood samples for assessment of HIV-1 RNA levels were collected at Baseline and Day 11.

Time Frame

Baseline (Day 1) and Day 11

Population Description

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

Intent-to-Treat Exposed (ITT-E) Population: all participants who received at least one dose of study medication and who had at least one post-Baseline measure of plasma HIV-1 RNA.

Reporting Groups

Description

Cohort I (DTG 50 mg OD)

Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).

Cohort II (DTG 50 mg BID)

Participants received DTG 50 mg twice a day (BID).

Measured Values

Cohort I (DTG 50 mg OD)

Cohort II (DTG 50 mg BID)

Participants Analyzed [Units: Participants]

27

24

Number of Participants Who Achieved HIV-1 RNA <400 Copies (c)/Milliliter (mL) or at Least 0.7 log10 c/mL Below Their Baseline Value at Day 11 [Units: Participants]

21

23

Statistical Analysis 1 for Number of Participants Who Achieved HIV-1 RNA <400 Copies (c)/Milliliter (mL) or at Least 0.7 log10 c/mL Below Their Baseline Value at Day 11

Groups [1]

Cohort I (DTG 50 mg OD)

Statistical Test Type [2]

Superiority or Other

percentage of participants [3]

78

95% Confidence Interval

58 to 91

[1]

Additional details about the analysis, such as null hypothesis and power calculation:

No text entered.

[2]

Details of power calculation, definition of non-inferiority margin, and other key parameters:

No text entered.

[3]

Other relevant estimation information:

The estimated value represents the percentage of participants with HIV-1 RNA <400 c/mL or at least 0.7 log10 c/mL below their Baseline value at Day 11.

Statistical Analysis 2 for Number of Participants Who Achieved HIV-1 RNA <400 Copies (c)/Milliliter (mL) or at Least 0.7 log10 c/mL Below Their Baseline Value at Day 11

Groups [1]

Cohort II (DTG 50 mg BID)

Statistical Test Type [2]

Superiority or Other

percentage of participants [3]

96

95% Confidence Interval

79 to 100

[1]

Additional details about the analysis, such as null hypothesis and power calculation:

No text entered.

[2]

Details of power calculation, definition of non-inferiority margin, and other key parameters:

No text entered.

[3]

Other relevant estimation information:

The estimated value represents the percentage of participants with HIV-1 RNA <400 c/mL or at least 0.7 log10 c/mL below their Baseline value at Day 11.

2. Secondary:

Mean Change From Baseline in Plasma HIV-1 RNA at Day 6 to 8, Day 11, Weeks 4, 12, 24, 48, 72, 96, From Week 108 Every 12 Weeks up to Study Completion [ Time Frame: Baseline; Day 6 to 8; Day 11; Weeks 4, 12, 24, 48, 72, 96, from 108 every 12 weeks up to study completion ]

Measure Type

Secondary

Measure Title

Mean Change From Baseline in Plasma HIV-1 RNA at Day 6 to 8, Day 11, Weeks 4, 12, 24, 48, 72, 96, From Week 108 Every 12 Weeks up to Study Completion

Measure Description

Mean change from Baseline in Plasma HIV-1 RNA was assessed on Day 6 to 8, Day 11, and Weeks 4, 12, 24, 48, 72, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, and 264 using data of the observed cases. Study Day 1 was considered as Baseline. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Time Frame

Baseline; Day 6 to 8; Day 11; Weeks 4, 12, 24, 48, 72, 96, from 108 every 12 weeks up to study completion

Population Description

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

ITT-E Population. Only those participants available at the indicated time points were analyzed (represented by n=X, X in the category titles).

Reporting Groups

Description

Cohort I (DTG 50 mg OD)

Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).

The number of participants with plasma HIV-1 RNA <400 c/mL or <50 c/mL was assessed at Weeks 4, 12, 24, 48, 72, and 96 per the Food and Drug Administration's Time to Loss of Virological Response (TLOVR) algorithm. Using the TLOVR algorithm, participants are considered to have failed on therapy if they never achieved confirmed RNA levels below the threshold, if they had confirmed rebound of RNA above the threshold, if they made a non-permitted change in background regimen, or if they permanently discontinued investigational product for any reason.

Time Frame

Baseline; Weeks 4, 12, 24, 48, 72, and 96

Population Description

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

ITT-E Population

Reporting Groups

Description

Cohort I (DTG 50 mg OD)

Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).

As of the data cut-off, Week 48 is the last time point which all participants in Cohort II would have had opportunity to reach if they had not discontinued prematurely. Only data to Week 48 were therefore analyzed using TLOVR.

[2]

As of the data cut-off, Week 48 is the last time point which all participants in Cohort II would have had opportunity to reach if they had not discontinued prematurely. Only data to Week 48 were therefore analysed using TLOVR.

Proportion of Participants Who Achieved Plasma HIV-1 RNA <400 c/mL and <50 c/mL From Week 48 Every 12 Weeks up to Study Completion [ Time Frame: From Week 48 every 12 weeks up to study completion ]

Measure Type

Secondary

Measure Title

Proportion of Participants Who Achieved Plasma HIV-1 RNA <400 c/mL and <50 c/mL From Week 48 Every 12 Weeks up to Study Completion

Measure Description

The number of participants with plasma HIV-1 RNA <400 c/mL or <50 c/mL was assessed at Weeks 48, 72, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, and 264 using data of observed cases. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).

Time Frame

From Week 48 every 12 weeks up to study completion

Population Description

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

ITT-E Population

Reporting Groups

Description

Cohort I (DTG 50 mg OD)

Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

ITT-E Population. Only those participants available at the indicated time points were analyzed (represented by n=X in the category titles).

Reporting Groups

Description

Cohort I (DTG 50 mg OD)

Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

The plasma DTG concentration immediately prior to dosing at steady state (C0) was assessed at Day 10, and Weeks 4 and 24. Blood samples for pharmacokinetic assessments were collected at pre-dose (within 15 minutes prior to dose).

Time Frame

Day 10; Weeks 4 and 24

Population Description

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

PK Parameter Population

Reporting Groups

Description

Cohort I (DTG 50 mg OD)

Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).

The tmax is defined as the time of occurrence of the maximum plasma concentration (Cmax). The tmax was assessed at Day 10. Blood samples for pharmacokinetic assessments were collected at pre-dose (within 15 minutes prior to dose) and 2, 3, 4, 8, and 24 hours post-dose on Day 10 for DTG 50 mg OD and pre-dose (within 15 minutes prior to dose) and 2, 3, 4 and 8 hours post morning dose and 12 hours post evening dose for DTG 50 mg BID.

Time Frame

Day 10

Population Description

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

PK Parameter Population

Reporting Groups

Description

Cohort I (DTG 50 mg OD)

Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).

Cohort II (DTG 50 mg BID)

Participants received DTG 50 mg twice a day (BID).

Measured Values

Cohort I (DTG 50 mg OD)

Cohort II (DTG 50 mg BID)

Participants Analyzed [Units: Participants]

25

23

Tmax of DTG [Units: Hours]Median (Full Range)

2.97
(1.97 to 7.92)

2.00
(0.00 to 7.87)

No statistical analysis provided for Tmax of DTG

9. Secondary:

AUC0-24 Assessment of DTG [ Time Frame: Day 10 ]

Measure Type

Secondary

Measure Title

AUC0-24 Assessment of DTG

Measure Description

AUC is defined as the area under the DTG concentration-time curve as a measure of drug exposure. AUC(0-24) is defined as the area under the concentration-time curve from time zero (pre-dose) to 24 hours. AUC0-24 of DTG was assessed at Day 10. Blood samples for pharmacokinetic assessments were collected at pre-dose (within 15 minutes prior to dose) and 2, 3, 4, 8, and 24 hours post-dose on Day 10 for DTG 50 mg OD and pre-dose (within 15 minutes prior to dose) and 2, 3, 4 and 8 hours post morning dose and 12 hours post evening dose for DTG 50 mg BID.

Time Frame

Day 10

Population Description

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

PK Parameter Population

Reporting Groups

Description

Cohort I (DTG 50 mg OD)

Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).

Number of Participants With the Indicated HIV-1 Associated Conditions, Excluding Recurrences [ Time Frame: From the day of the first dose of study drug until study completion (median 605 days for Cohort I, median 1181 days for Cohort II) ]

Measure Type

Secondary

Measure Title

Number of Participants With the Indicated HIV-1 Associated Conditions, Excluding Recurrences

Measure Description

The number of participants with post-Baseline emergent HIV-1 disease progression (Acquired immunodeficiency syndrome (AIDS) or death) was assessed per the Centers for Disease Control and Prevention (CDC) 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. The CDC classifies HIV infection as Category A (participants with asymptomatic HIV infection, acute HIV infection with accompanying illness, or persistent generalized lymphadenopathy), Category B (participants with symptomatic non-AIDS condition, i.e., conditions that are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or conditions are considered by physicians to have a clinical course or to require management that is complicated by HIV infection), and Category C (includes AIDS indicator conditions as defined by diagnostic or presumptive measures).

Time Frame

From the day of the first dose of study drug until study completion (median 605 days for Cohort I, median 1181 days for Cohort II)

Population Description

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

ITT-E Population. Participant may have more than one HIV associated condition. Each condition is counted only once per participant, regardless of recurrence.

Reporting Groups

Description

Cohort I (DTG 50 mg OD)

Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).

Cohort II (DTG 50 mg BID)

Participants received DTG 50 mg twice a day (BID).

Measured Values

Cohort I (DTG 50 mg OD)

Cohort II (DTG 50 mg BID)

Participants Analyzed [Units: Participants]

27

24

Number of Participants With the Indicated HIV-1 Associated Conditions, Excluding Recurrences [Units: Participants]

Category B, Candidiasis, oropharyngeal

3

2

Category B, Hairy leukoplakia, oral

2

0

Category B, Herpes Zoster

2

0

Category C, Herpes simplex

1

0

Category C, Candidiasis, esophageal

0

1

Category C, Cytomegalovirus retinitis

0

1

Category C, Kaposi's sarcoma

1

0

Category C, Lymphoma, Burkitt's

0

1

Category C, Lymphoma, immunoblastic

1

0

Death, Brain mass

1

0

Death, Completed suicide

0

1

Death, Febrile bone marrow aplasia

1

0

Death, Immunoblastic lymphoma

1

0

Death, Acute pulmonary oedema

1

0

Death, Anaemia

0

1

Death, Haemochromatosis

0

1

Death, Hepatic fibrosis

0

1

Other: Cryptosporidiosis, acute intestinal

0

1

Other: leukoplasia of both side of the tongue

1

0

No statistical analysis provided for Number of Participants With the Indicated HIV-1 Associated Conditions, Excluding Recurrences

11. Secondary:

Number of Participants With HIV-1 Associated Disease Progression With the Indicated Shifts to CDC Class C or Death [ Time Frame: From the day of the first dose of study drug until study completion (median 605 days for Cohort I, median 1181 days for Cohort II) ]

Measure Type

Secondary

Measure Title

Number of Participants With HIV-1 Associated Disease Progression With the Indicated Shifts to CDC Class C or Death

Measure Description

The number of participants with HIV-1 disease progression (AIDS or death) was assessed per the CDC 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. The CDC classifies HIV infection as Category A (participants with asymptomatic HIV infection, acute HIV infection with accompanying illness, or persistent generalized lymphadenopathy), Category B (participants with symptomatic non-AIDS condition, i.e., conditions that are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or conditions are considered by physicians to have a clinical course or to require management that is complicated by HIV infection), and Category C (includes AIDS indicator conditions as defined by diagnostic or presumptive measures).

Time Frame

From the day of the first dose of study drug until study completion (median 605 days for Cohort I, median 1181 days for Cohort II)

Population Description

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

ITT-E Population.

Reporting Groups

Description

Cohort I (DTG 50 mg OD)

Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).

Cohort II (DTG 50 mg BID)

Participants received DTG 50 mg twice a day (BID).

Measured Values

Cohort I (DTG 50 mg OD)

Cohort II (DTG 50 mg BID)

Participants Analyzed [Units: Participants]

27

24

Number of Participants With HIV-1 Associated Disease Progression With the Indicated Shifts to CDC Class C or Death [Units: Participants]

From CDC class A to CDC class C

0

2

From CDC class B to CDC class C

0

2

From CDC class C to new CDC class C

1

0

From CDC Class A, B, or C to death

3

2

No statistical analysis provided for Number of Participants With HIV-1 Associated Disease Progression With the Indicated Shifts to CDC Class C or Death

PDVF is defined in relation to Baseline plasma HIV-1 RNA levels: at Day 11, a decrease of <0.7 log10 c/mL unless <400 c/mL; at Weeks 8 to <16, a decrease of <1.0 log10 c/mL unless <400 c/mL or an increase of >= 1.0 log10 c/mL from nadir; and at or after Week 16, ≥400 c/mL. PDVF at Day 11 was based on a single plasma HIV-1 RNA evaluation and did not require confirmation. Confirmation testing was required for visits at or after Week 8. For the combination treatment phase, all HIV-1 RNA samples that meet a criterion for suspected PDVF must be confirmed by a second measurement performed at least 1 week but not more than 4 weeks apart from the date of the original sample.

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

ITT-E Population

Reporting Groups

Description

Cohort I (DTG 50 mg OD)

Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).

Number of Participants With the Indicated Genotypic Resistance at Baseline [ Time Frame: Baseline ]

Measure Type

Secondary

Measure Title

Number of Participants With the Indicated Genotypic Resistance at Baseline

Measure Description

At Baseline, the integrase genotypic results were used to document resistance to raltegravir (RAL) and for the allocation of participants to one of two genotypic groups according to their RAL signature mutations to ensure a broad range of sensitivity to DTG. These results were not used to pre-define subgroup for analysis.

Time Frame

Baseline

Population Description

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

ITT-E Population

Reporting Groups

Description

Cohort I (DTG 50 mg OD)

Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).

Cohort II (DTG 50 mg BID)

Participants received DTG 50 mg twice a day (BID).

Measured Values

Cohort I (DTG 50 mg OD)

Cohort II (DTG 50 mg BID)

Participants Analyzed [Units: Participants]

27

24

Number of Participants With the Indicated Genotypic Resistance at Baseline [Units: Participants]

Q148 + 2

3

2

Q 148 + 1

4

8

Mixture

2

1

Y143

12

6

N155

4

6

Other

2

1

No statistical analysis provided for Number of Participants With the Indicated Genotypic Resistance at Baseline

14. Secondary:

Median Fold Change in Sensitivity to DTG by the Baseline (Day 1) IN Mutational Group [ Time Frame: Baseline (Day 1) ]

Measure Type

Secondary

Measure Title

Median Fold Change in Sensitivity to DTG by the Baseline (Day 1) IN Mutational Group

Measure Description

Summary of median fold change in sensitivity to DTG by Integrase (IN) mutational group was assessed. The IN mutational group comprises of the following mutations: Q148 +2, Q148 +1, mixture (participants with virus containing more than one Y143, Q148 or N155 mutation at Day 1), Y143, N155, other (participants with virus having no mutations at codons 143, 148, or 155 at Day 1). Fold change (FC) is the fold change in 50% Inhibitory Concentration (IC50) relative to the wild-type control virus.

Time Frame

Baseline (Day 1)

Population Description

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

ITT-E Population

Reporting Groups

Description

Cohort I (DTG 50 mg OD)

Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).

Cohort II (DTG 50 mg BID)

Participants received DTG 50 mg twice a day (BID).

Measured Values

Cohort I (DTG 50 mg OD)

Cohort II (DTG 50 mg BID)

Participants Analyzed [Units: Participants]

27

24

Median Fold Change in Sensitivity to DTG by the Baseline (Day 1) IN Mutational Group [Units: Percentage]Median (Full Range)

Q148 + 2, n=3, 2

21
(14 to 35)

4
(2.1 to 6.0)

Q148 + 1, n=4, 8

5.5
(3.3 to 25)

5.5
(4.1 to 8.2)

Mixture, n=2, 1

7.8
(6.5 to 9.1)

9.48
(9.48 to 9.48)

Y143, n=12, 6

1.1
(0.6 to 1.4)

1.2
(0.92 to 1.8)

N155, n=4, 6

1.8
(1.5 to 5.1)

2.3
(1.3 to 4.0)

Other, n=2, 1

1.2
(0.9 to 1.5)

0.87
(0.87 to 0.87)

No statistical analysis provided for Median Fold Change in Sensitivity to DTG by the Baseline (Day 1) IN Mutational Group

15. Secondary:

Number of Participants With the Indicated Treatment-emergent Integrase (IN) Mutations Detected at the Time of Protocol-defined Virologic Failure (PDVF) as a Measure of Genotypic Resistance [ Time Frame: From Baseline (Day 1) until study completion (median 605 days for Cohort I, median 1181 days for Cohort II) ]

Measure Type

Secondary

Measure Title

Number of Participants With the Indicated Treatment-emergent Integrase (IN) Mutations Detected at the Time of Protocol-defined Virologic Failure (PDVF) as a Measure of Genotypic Resistance

Measure Description

An analysis of changes at specific amino acids in the IN coding region associated with resistance to raltegravir, elvitegravir, or DTG was performed at Day 1 and at the time of PDVF. PDVF is defined in relation to Baseline plasma HIV-1 RNA levels: at Day 11, a decrease of <0.7 log10 c/mL unless <400 c/mL; at Weeks 8 to <16, a decrease of <1.0 log10 c/mL unless <400 c/mL or an increase of >= 1.0 log10 c/mL from nadir; and at or after Week 16, ≥400 c/mL. PDVF at Day 11 was based on a single plasma HIV-1 RNA evaluation and did not require confirmation. Confirmation testing was required for visits at or after Week 8. For the combination treatment phase, all HIV-1 RNA samples that meet a criterion for suspected PDVF must be confirmed by a second measurement performed at least 1 week but not more than 4 weeks apart from the date of the original sample.

Time Frame

From Baseline (Day 1) until study completion (median 605 days for Cohort I, median 1181 days for Cohort II)

Population Description

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).

Cohort II (DTG 50 mg BID)

Participants received DTG 50 mg twice a day (BID).

Measured Values

Cohort I (DTG 50 mg OD)

Cohort II (DTG 50 mg BID)

Participants Analyzed [Units: Participants]

18

7

Number of Participants With the Indicated Treatment-emergent Integrase (IN) Mutations Detected at the Time of Protocol-defined Virologic Failure (PDVF) as a Measure of Genotypic Resistance [Units: Participants]

Any

11

5

E138T

0

1

N155H

3

4

T97A

2

0

E92E/Q

0

1

G140S

3

0

L74I/M

1

0

Q148H

2

0

E138E/A

1

0

E138E/K

1

2

L74I/M/I

1

0

L74M

1

0

L74I

1

0

T97T/A

0

2

Q148R

1

0

S147G

3

0

E92E/V

0

1

L68L/I

1

0

No statistical analysis provided for Number of Participants With the Indicated Treatment-emergent Integrase (IN) Mutations Detected at the Time of Protocol-defined Virologic Failure (PDVF) as a Measure of Genotypic Resistance

16. Secondary:

Number of Participants With the Indicated Fold Increase in DTG FC (Fold Change in IC50 Relative to Wild-type Virus) Between Baseline and the Time of PDVF, as a Measure of Post-Baseline Phenotypic Resistance [ Time Frame: From Baseline (Day 1) until study completion (median 605 days for Cohort I, median 1181 days for Cohort II) ]

Measure Type

Secondary

Measure Title

Number of Participants With the Indicated Fold Increase in DTG FC (Fold Change in IC50 Relative to Wild-type Virus) Between Baseline and the Time of PDVF, as a Measure of Post-Baseline Phenotypic Resistance

Measure Description

The FC in IC50 (50% inhibitory concentration) for DTG relative to wild-type virus was determined for virus isolated at Baseline and at the time of PDVF.The number of participants with the indicated change (ratio) in the two values at the time of PDVF is presented. PDVF is defined in relation to Baseline plasma HIV-1 RNA levels: at Day 11, a decrease of <0.7 log 10 c/mL unless <400 c/mL; at Weeks 8 to <16, a decrease of <1.0 log 10 c/mL unless <400 c/mL or an increase of >=1.0 log 10 c/mL from nadir; and at or after Week 16, ≥400 c/mL . PDVF at Day 11 was based on a single plasma HIV-1 RNA evaluation and did not require confirmation. Confirmation testing was required for visits at or after Week 8. For the combination treatment phase, all HIV-1 RNA samples that meet a criterion for suspected PDVF must be confirmed by a second measurement performed at least 1 week but not more than 4 weeks apart from the date of original sample.

Time Frame

From Baseline (Day 1) until study completion (median 605 days for Cohort I, median 1181 days for Cohort II)

Population Description

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

PDVF Phenotypic Resistance Populations: all participants in the ITT-E Population with available on-treatment phenotypic resistance data at the time of PDVF failure. Only participants with both Baseline and PDVF time-point DTG phenotypic data were considered for analysis.

Reporting Groups

Description

Cohort I (DTG 50 mg OD)

Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).

Cohort II (DTG 50 mg BID)

Participants received DTG 50 mg twice a day (BID).

Measured Values

Cohort I (DTG 50 mg OD)

Cohort II (DTG 50 mg BID)

Participants Analyzed [Units: Participants]

17

7

Number of Participants With the Indicated Fold Increase in DTG FC (Fold Change in IC50 Relative to Wild-type Virus) Between Baseline and the Time of PDVF, as a Measure of Post-Baseline Phenotypic Resistance [Units: Participants]

<1 fold

3

0

1-<2 fold

4

2

2-<4 fold

1

0

4-<8 fold

1

2

>=8 fold

8

3

No statistical analysis provided for Number of Participants With the Indicated Fold Increase in DTG FC (Fold Change in IC50 Relative to Wild-type Virus) Between Baseline and the Time of PDVF, as a Measure of Post-Baseline Phenotypic Resistance

17. Secondary:

Number of Participants With the Indicated Grade 3 and Grade 4 Clinical Chemistry Toxicities [ Time Frame: From start of study treatment until the end of treatment visit for each participant, up to Week 264 for Cohort I and up to Week 228 for Cohort II ]

Measure Type

Secondary

Measure Title

Number of Participants With the Indicated Grade 3 and Grade 4 Clinical Chemistry Toxicities

From start of study treatment until the end of treatment visit for each participant, up to Week 264 for Cohort I and up to Week 228 for Cohort II

Population Description

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

Safety Population: all participants that took at least one dose of DTG

Reporting Groups

Description

Cohort I (DTG 50 mg OD)

Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).

Cohort II (DTG 50 mg BID)

Participants received DTG 50 mg twice a day (BID).

Measured Values

Cohort I (DTG 50 mg OD)

Cohort II (DTG 50 mg BID)

Participants Analyzed [Units: Participants]

27

24

Number of Participants With the Indicated Grade 3 and Grade 4 Clinical Chemistry Toxicities [Units: Participants]

Albumin, Grade 3

0

0

Albumin, Grade 4

0

0

Alkaline Phosphatase, Grade 3

0

0

Alkaline Phosphatase, Grade 4

0

0

Amylase, Grade 3

1

2

Amylase, Grade 4

1

0

Aspartate Amino Transferase, Grade 3

0

0

Aspartate Amino Transferase, Grade 4

0

0

Carbon dioxide content/Bicarbonate, Grade 3

0

0

Carbon dioxide content/Bicarbonate, Grade 4

0

0

Creatinine, Grade 3

0

0

Creatinine, Grade 4

0

0

Creatinine Clearance, estimated, Grade 3

0

0

Creatinine Clearance, estimated, Grade 4

0

0

Hypercalcemia, Grade 3

0

0

Hypercalcemia, Grade 4

0

0

Hyperglycaemia, Grade 3

0

0

Hyperglycaemia, Grade 4

0

0

Hyperkalemia, Grade 3

0

0

Hyperkalemia, Grade 4

0

0

Hypernatremia, Grade 3

1

0

Hypernatremia, Grade 4

0

0

Hypocalcemia, Grade 3

0

0

Hypocalcemia, Grade 4

0

0

Hypoglycaemia, Grade 3

1

0

Hypoglycaemia, Grade 4

0

1

Hypokalemia, Grade 3

0

0

Hypokalemia, Grade 4

0

0

Hyponatremia, Grade 3

0

0

Hyponatremia, Grade 4

0

0

LDL Cholesterol, Grade 3

2

1

LDL Cholesterol, Grade 4

0

0

Magnesium, Grade 3

0

0

Magnesium, Grade 4

0

0

Phosphorus inorganic, Grade 3

4

3

Phosphorus inorganic, Grade 4

0

0

Total Bilirubin, Grade 3

0

2

Total Bilirubin, Grade 4

0

1

Alanine Amino Transferase ,Grade 3

0

1

Alanine Amino Transferase ,Grade 4

0

0

Calcium,Grade 3

0

0

Calcium,Grade 4

0

0

Chloride,Grade 3

0

0

Chloride,Grade 4

0

0

Cholesterol,Grade 3

1

1

Cholesterol,Grade 4

0

0

Creatine Kinase,Grade 3

0

0

Creatine Kinase,Grade 4

0

0

Direct Bilirubin,Grade 3

0

0

Direct Bilirubin,Grade 4

0

0

Glucose,Grade 3

1

0

Glucose,Grade 4

0

1

HDL Cholesterol direct,Grade 3

0

0

HDL Cholesterol direct,Grade 4

0

0

Lipase,Grade 3

2

3

Lipase,Grade 4

1

1

Potassium,Grade 3

0

0

Potassium,Grade 4

0

0

Sodium,Grade 3

1

0

Sodium,Grade 4

0

0

Total Cholesterol/HDLratio, Grade 3

0

0

Total Cholesterol/HDLratio, Grade 4

0

0

Triglycerides,Grade 3

0

2

Triglycerides,Grade 4

0

0

Urea/BUN,Grade 3

0

0

Urea/BUN,Grade 4

0

0

No statistical analysis provided for Number of Participants With the Indicated Grade 3 and Grade 4 Clinical Chemistry Toxicities

18. Secondary:

Number of Participants With the Indicated Grade 3 and Grade 4 Hematological Toxicities [ Time Frame: From start of study treatment until the end of treatment visit for each participant, up to Week 264 for Cohort I and up to Week 228 for Cohort II ]

Measure Type

Secondary

Measure Title

Number of Participants With the Indicated Grade 3 and Grade 4 Hematological Toxicities

From start of study treatment until the end of treatment visit for each participant, up to Week 264 for Cohort I and up to Week 228 for Cohort II

Population Description

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

Safety Population: all participants that took at least one dose of DTG

Reporting Groups

Description

Cohort I (DTG 50 mg OD)

Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).

Cohort II (DTG 50 mg BID)

Participants received DTG 50 mg twice a day (BID).

Measured Values

Cohort I (DTG 50 mg OD)

Cohort II (DTG 50 mg BID)

Participants Analyzed [Units: Participants]

27

24

Number of Participants With the Indicated Grade 3 and Grade 4 Hematological Toxicities [Units: Participants]

Hemoglobin, Grade 3

0

1

Hemoglobin, Grade 4

0

0

Platelet count, Grade 3

0

0

Platelet count, Grade 4

0

0

Total Neutrophils, Grade 3

0

0

Total Neutrophils, Grade 4

0

2

White Blood Cell count, Grade 3

0

0

White Blood Cell, Grade 4

0

1

No statistical analysis provided for Number of Participants With the Indicated Grade 3 and Grade 4 Hematological Toxicities

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts
the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release
and can embargo communications regarding trial results for a period that is less than or equal to 60 days.
The sponsor cannot require changes to the communication and cannot extend the embargo.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release
and can embargo communications regarding trial results for a period that is more than 60 days but less than
or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed.

Restriction Description:
GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.